Acute Respiratory Distress Syndrome (ARDS) is a devastating condition with mortality of 40-50% that occurs in a minority of patients after an acute insult such as sepsis, aspiration, trauma, pneumonia, or multiple transfusions. In the United States alone, there are an estimated 170,000 cases per year. Although there have been significant scientific advances in understanding the clinical and pathophysiologic aspects of the syndrome, there remains no specific therapy for ARDS. Moreover, although major risk factors for development of ARDS are known, it remains unclear why individuals with identical predisposing conditions differ in their risk of developing ARDS or in their clinical outcome (i.e., survival) following ARDS. Also, recent results from our present study and others suggest that genetic susceptibility is also involved in the development of ARDS. The objective of this competing continuing proposal is to assess genetic, phenotypic and clinical biomarkers in ARDS risks and clinical outcomes. The specific aims of the proposal are to assess: 1) the role of known functional polymorphisms and haplotypes in genes involved in inflammatory/anti-inflammatory response and extracellular matrix degrading (TNF-alpha, TNF-beta, IL-6, IL- 10, NFkBIA, MMP-1, MMP-3, MMP-9, and MMP-12) in the development and outcomes of ARDS; 2) To assess the roles of genetic factors in modifying the effects of important clinical factors in the risks and clinical outcomes of ARDS; and 3) To assess the role of candidate phenotypic markers in the risks and clinical outcomes of ARDS patients. To address these aims, the research design consists of a large nested case- control study deriving from a prospective cohort of critically ill patients at risk for ARDS. Candidate gene polymorphism from relevant pathways will be assessed, and haplotypes will be inferred with an in silico algorithm. In Aim 3, we will examine potentially important clinical and phenotypic markers, and their relationship with ARDS risks and outcomes, and in relation to candidate polymorphisms. This research has important public health implications as the identification of genetic and phenotypic biomarkers in ARDS will help with risk assessment and identification of patients who may benefit most from specific interventions. This study takes advantage of a large prospectively collected cohort of ARDS patients and controls with detailed clinical information, using a mulidisciplinary approach with high translational potential.